Metabolic Disorders During Pregnancy and the Risk of Childhood Obesity

Early life programming, through gestational diabetes or other metabolic disorders during pregnancy, may contribute to the development of childhood obesity.

Childhood obesity is a multifactorial disease process with an upward trend over the years. Prior evidence suggests possible exposure to in utero maternal obesity or gestational diabetes mellitus (GDM) might have a role. Previous studies in animals determined predisposed obesity comes from the disruption of the development of the hypothalamus. Other studies in adults have shown a potential marker of risk for obesity might be due to an alteration in the hypothalamic response to oral glucose.

The study wanted to explore the “impact of in utero exposure to maternal obesity and GDM on glucose-linked changes in cerebral BL *CBF) in the hypothalamus, the key brain region for body weight regulation and the region where maternal-fetal programming effects were shown to occur in animal models.” Also, the study was to assess “whether an alteration in the hypothalamic response to glucose in children would predict greater increases in adiposity one year later.” Ninety-one children, 7-11 years of age, were used from the Brain Child Study. Proper documentation of exposure to maternal GDM or normal glucose levels during pregnancy had to be present, leaving 53 children who were GDM-exposed and 38 unexposed. For mothers, the diagnosis of maternal GDM was recorded, along with calculating maternal prepregnancy BMI and documenting gestational weight gain over the pregnancy.

There was a total of 3 visits; the third visit was added to the study protocol after the study began, accounting for fewer patients returning for the follow-up visit. At the first visit, height, weight, waist and hip circumferences and percent body fat were measured. BMI was calculated, and a physical exam assessed the Tanner stage. At visit 2, the children underwent MRI scanning. The researchers got a baseline pulsed arterial spin labeling (PASL) scan, then a high-resolution anatomical scan. Another PASL scan was taken 10 minutes after the children ingested a standardized glucose drink (max 75g). From each PASL scan, the researchers calculated regional blood flow in the hypothalamus. Similarly, before and after glucose ingestion, they also calculated mean CBF across the whole brain. Finally, at the third visit, baseline measurements at visit one were repeated.

Linear regression models were used and were done for each relationship assessed. Analyses were performed with and without adjustments for things such as age, sex, BMI Z score, maternal exposure variables, and for any potential confounders based on socioeconomic status. The study defined statistical significance as P < 0.05.

Of the 53 children who were GDM-exposed, 15 were exposed < 26 weeks gestation and 38 children > 26 weeks gestation. 1 hour after the 50-g glucose challenge during pregnancy, in those GDM diagnosed < 26 weeks gestation, post-glucose levels were 178 + 37 mg/dL, compared to those diagnosed with GDM > 26 weeks gestation, 145 + 40 mg/dL (P = 0.02) and the unexposed group, 115 + 23 mg/dL (P < 0.001). GDM exposed children versus unexposed had similar hypothalamic responses to glucose (P = 0.50). But when gestational age at diagnosis of GDM was divided at 26 weeks, children GDM exposed < 26 weeks gestation had a significantly higher hypothalamic response than children with GDM > 26 weeks and unexposed (P = 0.03). There was an increase in children’s hypothalamic response to glucose when exposed to GDM at an earlier gestational age.

Further adjusting for age, sex, and BMI Z score, the data remained significant. With adjustment for glucose levels from the challenge test, the early GDM group no longer had a significant association (P = 0.72), implying the association may be influenced by the severity of GDM.

Assessing maternal prepregnancy BMI with a child’s hypothalamic response to glucose, there was a positive association (P = 0.03). With adjustment for GDM exposure, the data was no longer significant. Throughout pregnancy, there was no significant association between gestational weight gain and hypothalamic response (P = 0.21). However, between the seven child adiposity measurements and maternal prepregnancy BMI, a positive association was determined. The significant association remained after adjustment for age, sex, and maternal GDM status. At the 1 year follow up, 44 children returned, with significant increases in BMI (P < 0.001), total body fat (P = 0.02), waist circumference (P < 0.001), and hip circumference (P < 0.001). An association was seen between a greater hypothalamic response to glucose at baseline and a greater increase in the child’s BMI at follow-up (P = 0.02). Furthermore, there was a significant association between maternal prepregnancy BMI and a greater increase in a child’s BMI (P = 0.03), but no association  

The authors believe that their findings give evidence that early life programming may contribute to the development of obesity. They found in utero exposure to maternal obesity or GDM diagnosed by 26 weeks’ gestation had a significant association with an increased hypothalamic response to glucose at ages 7-11 years old. Consequently, this response is predictive of a greater increase in the child’s adiposity one year later. The authors also suggest the GDM cases who were diagnosed earlier in pregnancy with greater severity of hyperglycemia might have a more significant role in fetal hypothalamic programming. Children exposed to GDM were found to specifically have higher abdominal adiposity, versus children exposed to a higher maternal prepregnancy BMI, who had a significant association with all measures of adiposity. This leads to the idea that there might be a stronger impact from maternal obesity versus maternal GDM on the tendency of developing obesity as a child. Again, multiple factors are leading to the development of childhood obesity, but two main factors found in this study which increase the risk of obesity are exposures to maternal GDM and obesity in utero. Proper discussions with mothers should take place before conception to decrease the risk of obesity in their children. Also, proper treatment of GDM during pregnancy plays a large role in controlling the mother’s hyperglycemia to decrease the risk of obesity later in life in their children.

Practice Pearl

• Childhood obesity is on an upward trend.
• Controlling maternal metabolic disorders during pregnancy may decrease the risk of obesity later in a child’s life.
• Determining a child’s risk factors for developing childhood obesity helps providers know which patients need initiation of lifestyle interventions.

Reference for “Metabolic Disorders During Pregnancy and the Risk of Childhood Obesity”:
Page, Kathleen, et al. Children Exposed to Maternal Obesity of Gestational Diabetes During Early Fetal Development Have Hypothalamic Alterations That Predict Future Weight Gain. Diabetes Care. 2019 May 21.

Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate

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